As human beings age, they begin to develop a variety of chronic diseases the etiologies of which remain unclear at this time. These chronic diseases affect virtually all organ systems of the body. Several animal models of chronic disease involve viral infection, especially retroviral infection. For example, murine leukemia viruses have been implicated in causing lymphoma, autoimmune and immunodeficiency diseases. The study of these types of animal models suggested that retroviruses play significant roles in those disease states. However, the extrapolation of findings within animal models to humans have not proven very successful in the identification of fully infectious retroviruses associated with chronic immunologic diseases outside of HTLV (with lymphoma), HIV (with AIDS), and HuLAV (with human B-cell, non-Hodgkins lymphoma (U.S. Pat. No. 5,108,920).
In searching for potential agents associated with other chronic diseases a vast array of human endogenous retroviral elements were discovered and characterized (Lower et al. Proc Natl Acad Sci 93:5177-5184 (1996); Tonjes et al. J Virol 73(11):9187-9195 (1999); Sverdlov Bioessays 22(2):161-171 (2000)). The closest class of endogenous retroviral element identified in humans to those associated with chronic disease in mouse disease models are the human endogenous retroviruses (HERV) (Wilier et al. Virus Genes 15(2):123-133 (1997)). Evidence for expression of HERV related genes or antibodies to HERV elements have been identified in a variety of chronic diseases such as terato carcinoma (Boller et al. J Virol 71:4581-4588 (1997); Boller et al. Virology 196:349-353 (1993)), lymphoma (Lower et al., (1996) supra), multiple sclerosis (Clerici et al. J Neuroimmunol 99(2):173-182 (1999); Trabattoni et al. J Neurovirol 6(Suppl 2):S38-41 (2000)), autoimmune rheumatic diseases (Nelson et al. Immunol Invest 28(4):277-289 (1999)), and most recently schizophrenia (Yolken et al. Brain Res Rev 31(2-3):193-199 (2000)). However, as human endogenous retroviral elements make up almost 1% of the human genome and each of these elements is highly related to other endogenous elements, their role in the pathogenesis of disease has been difficult to assess.
Despite the advances in identification of retroviruses and other agents associated with disease, identification of the causative or associated agents of many diseases remains elusive. Certain types of lymphoid malignancies are among such diseases. Three major categories of lymphoid malignancies have been recognized based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkins lymphoma. B-cell and T-cell/NK neoplasms are often referred to as non-Hodgkins lymphomas. Both lymphomas and lymphoid leukemias are included in within these classifications because both solid and circulating phases are present in many lymphoid neoplasms. Within the B- and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms. The aggressive lymphomas are particularly difficult to diagnose at an early stage, largely due to their primarily asymptomatic nature. Thus, diagnosis of the aggressive non-Hodgkins lymphomas is normally at a stage late in the course of disease, and the prognosis is normally poor.
Mantle cell lymphoma is an example of an aggressive, non-Hodgkins lymphoma. Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). Mantle cell lymphoma is generally characterized by CD5-positive follicular mantle B cells, a translocation of chromosomes 11 and 14, and an overexpression of the cyclin D1 protein. Like the low-grade lymphomas, mantle cell lymphoma appears incurable with anthracycline-based chemotherapy and occurs in older patients with generally asymptomatic advanced-stage disease. However, the median survival is significantly shorter (3-5 years) than that of other lymphomas; hence this histology is now considered to be an aggressive lymphoma. A diffuse pattern and the blastoid variant have an aggressive course with shorter survival, while the mantle zone type may have a more indolent course. It is unclear which chemotherapeutic approach offers the best long-term survival in this clinicopathologic entity; refractoriness to chemotherapy is a usual feature. Many investigators are exploring high-dose therapy with stem cell/marrow support or the use of interferon or anti-CD20 antibodies after CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.
Identification of agents of chronic disease such as cancer are important, not only for diagnosis of affected patients and development of anti-cancer drugs, but also in the prevention of the spread of chronic disease where causative agent is transmissible, e.g., through blood transfusion, transplant of infected tissues, sharing or re-use of needles, sexual contact, and the like. Transmission of lymphoma from a donor to a recipient can occur due to direct infection with the virus.
There is a need in the field for identification of agents that are associated with (and thus can serve as a marker for) or cause cancers of unknown etiology. Furthermore, identification of agents associated with chronic diseases, such as cancer, allow for screening of biological materials for the associated agent prior to use (e.g., screening of blood, blood products, tissues, and the like). The present invention addresses this need.